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Osteoporosis is a common, age-related disease caused by imbalanced bone remodeling. Current treatments either shut down bone resorption or robustly stimulate bone formation. Here, we describe a novel compound that inhibits osteoclast activity without causing apparent disruptions to bone formation by targeting both c-FMS (i.e., osteoclast differentiation) and αvβ3 integrin (i.e., osteoclastic bone resorption) receptors. We show that human serum albumin (HSA)-conjugated M-CSF RGD protein (M-CSF RGD -HSA) effectively inhibits the activity of both receptors, with a three-fold higher serum half-life compared to the unconjugated M-CSF RGD . We then treated ovariectomized mice with different doses of M-CSF RGD -HSA, alendronate, or a monospecific control protein. The bispecific M-CSF RGD -HSA was superior to a monospecific control in alleviating bone loss and reducing osteoclast distribution and function. M-CSF RGD -HSA and alendronate effectively prevented ovariectomy-induced bone loss, but M-CSF RGD -HSA had a milder inhibitory effect on osteoclast distribution and activity. Moreover, alendronate halted bone formation, while M-CSF RGD -HSA-treated mice showed an increased level of serum amino-terminal propeptide of type I collagen, a bone formation marker. Our data indicate that the mild reduction in osteoclast activity facilitated by the bispecific M-CSF RGD -HSA allows the maintenance of certain levels of bone formation and may be superior to treatments that induce osteoclast depletion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)